A Rare Cause of Intestinal Dysmotility in a Patient with Small Cell Lung Cancer

The diagnosis in this case was paraneoplastic enteric neuropathy. Anti-Hu antibody was positive (>1:640). Despite the small bowel resection, he continued to have symptoms of ileus and was placed on total parental nutrition (TPN). The patient was started on high...

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The diagnosis in this case was paraneoplastic enteric neuropathy. Anti-Hu antibody was positive (>1:640). Despite the small bowel resection, he continued to have symptoms of ileus and was placed on total parental nutrition (TPN). The patient was started on high dose methylprednisolone and was slowly able to modestly increase his oral intake but still required TPN. He was started on salvage gemcitabine for platinum refractory high grade neuroendocrine cancer. Unfortunately, he developed progressive disease after 2 months of therapy. The Hu antibody titer remained elevated at >1:640. He declined further treatment and died on hospice 1 month later, 4 months after presentation with the small bowel obstruction and 8 months after diagnosis with high-grade neuroendocrine carcinoma. 

Paraneoplastic enteric neuropathy (also known as paraneoplastic GI dysmotility) is a rare subtype of paraneoplastic neuropathy associated primarily with SCLC, although other cancer types have been seen (thymoma, carcinoid). The association between a cancer diagnosis and enteric neuropathy appears to have been first made in the late 1980’s.¹ The etiology appears to be autoimmune, with many associated onconeural antibodies. The most common, and first described, is the anti-Hu antibody, also known as anti-neuronal nuclear antibody, type 1 (ANNA-1). The Hu protein family is expressed in all parts of the nervous system, and in SCLC, but also in other tumor types. Up to 30% of patients with anti-Hu antibodies have symptoms that can be related to GI dysmotility. The voltage-gated calcium channels (VGCC) regulate acetylcholine release in the peripheral nervous system, and antibodies to these channels are commonly associated with syndromes such as Lambert-Eaton syndrome; however the N-type VGCC can be associated with GI dysmotility. Anti-Yo (Purkinje cell antibody type 1 – PCA-1) is a less common cause of paraneoplastic GI dysmotility, as are CRMP-5 or amphiphysin.

Pareneoplastic GI dysmotility is usually a subacute, rapidly progressive clinical problem that leaves afflicted patients significantly debilitated within months. The epidemiology of these disorders is relatively poorly defined; however, evidence suggests an older age of onset.^2,3 The majority of patients will present with GI dysmotility issues prior to their underlying tumor being diagnosed, often by over 8 months.³

Gastroparesis and other non-specific peristaltic abnormalities are among the most common syndromes described; however, chronic intestinal pseudo-obstruction is the most dramatic presentation, and may be the single most common presentation. Constipation is also frequent.

A high index of suspicion of a paraneoplastic cause is needed, particularly in any patient who presents with GI dysmotility and undue wasting or weight loss. Paraneoplastic antibody testing should be considered along with confirmatory tests for GI dysmotility (gastric emptying studies, colonic transit time, manometry). The detection of onconeural antibodies in a patient with no previously known diagnosis of neoplasm should prompt an aggressive search for an occult tumor (including PET, PET/CT, bronchoscopy, even surgical exploration). Ongoing monitoring should be continued if no tumor is found on initial evaluation.

As with all paraneoplastic syndromes, the management of paraneoplastic enteric neuropathy relies on treatment of the underlying neoplasm. Prognosis is poor, and patients frequently die within a year of diagnosis. Treatment of the underlying malignancy frequently leads to stabilization of disease, without significant improvement in gut motility, even if the tumor is in remission.⁴ Aggressive immunosuppression (high-dose steroids, plasmapheresis, cyclophosphamide) is rarely associated with success (unlike this case), as the symptoms are generally due to irreversible neuronal damage.⁵

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References

1. DiBaise JK. Paraneoplastic gastrointestinal dysmotility: when to consider and how to diagnose. Gastroenterol Clin North Am. 2011;40(4):777-786.
2. Chinn JS, Schuffler MD. Paraneoplastic visceral neuropathy as a cause of severe gastrointestinal motor dysfunction. Gastroenterology. 1988;95(5):1279-1286.
3. Lee HR, Lennon VA, Camilleri M, Prather CM. Paraneoplastic gastrointestinal motor dysfunction: clinical and laboratory characteristics. Am J Gastroenterol. 2001;96(2):373-379.
4. Sodhi N, Camilleri M, Camoriano JK, et al. Autonomic function and motility in intestinal pseudoobstruction caused by a paraneoplastic syndrome. Dig Dis Sci. 1989;34(12):1937-1942.
5. Vernino S, O’Neill BP, Marks RS, et al. Immunomodulatory treatment trial for paraneoplastic neurological disorders. Neuro Oncol. 2004;6(1):55-62.